1. Field of the Invention
This invention relates to biodegradable composites for internal use. That is, it relates to composites made up of biodegradable substrate and a biodegradable reinforcement which can be used internally in the body of a human or animal for bone fixation or the like. In this use, the composites gradually completely degrade to soluble products. In preferred embodiments, this invention relates to the use of poly(ortho esters) as the erodible substrate and to the use of calcium-sodium metaphosphate fibers as the reinforcement in such composites.
2. Introduction and Summary of Background Art
Metal plates, pins, rods, and screws are used for rigid internal fixation of bones and tendons which have been damaged by trauma or reconfigured surgically to correct defects occurring congenitally, developmentally or as the result of disease. These devices are most commonly fabricated from stainless steel and align bone fragments by bringing their edges into close proximity. Due to device structural stiffness they control relative motion to allow bone union. For healing, the stabilization must persist for several weeks or months without device breakage or loosening. While the level of relative motion that can be tolerated has not been thoroughly determined, it is understood that gross motion at the fracture site will result in non-union of the bone fragments.
While metal devices of the type well known in the art can hold fragments in close proximity, they may at times interfere with proper healing. This has been traced to their extreme rigidity. It has been demonstrated that completion of healing is prevented by permanent highly rigid fixation of the bone fragments. This is because much of the load that is normally carried by the bone is transferred across the fracture site by the implant. This load transfer is brought about by a mismatch between the elastic modulus of the bone and the metal implant E.sub.bone =6-20 Gpa and E.sub.metal =100-200 Gpa). The stress-shielded bone heals incompletely or may even remodel so that the shielded area is susceptible to refracture when the implant is removed.
Another problem inherent in the metal fixation implants used heretofore is that they generally need to be surgically removed after they have served their desired function. This is done to eliminate pain (which can be caused by local corrosion, tissue pressure or friction related to loosening), or at the suggestion of the surgeon where he or she believes this represents the patient's best interest. This removal involves a second surgery, with its attendant costs and risks.
Some attempts at reducing the rigidity of fixation implants have included the use of permanent implants made from titanium alloys, polymers and carbon-reinforced polymers such as nylon, polyether sulphone and polymethylmethacrylate. These implants lessen stress shielding but still may need to be removed after the bone heals.
Beginning in 1971, investigators reported the possibility of employing implants fabricated from materials which gradually break down or dissolve when placed in the body. An implant formed of a biodegradable material, which meets basic design criteria, including biocompatibility (sterilizability and low toxicity), compatibility for intraoperative reshaping (where needed) and sufficient initial strength and stiffness, has two major advantages over conventional implants: (a) It allows gradual load transfer to the healing bone as it degrades and (b) It eliminates the need for surgical removal.
The earliest reported use of an resorbable polymer for fracture fixation was described by Kulkarni et al. in the J. Mater. Res. 5, pp. 169-181 (1971). He successfully used extruded rods of poly(lactic acid) to reduce mandibular fractures in dogs.
More recently the number of reports dealing with the use of biodegradable polymers and composites for fracture fixation has increased dramatically. At least 63 articles on the subject have appeared as of the date of this application. The most common materials of construction for these articles are poly(lactic acid) and poly(glycolic acid). Other materials also have been used. Typical references in the literature and the materials they describe include:
H. Alexander et al. "Development of new methods for phalangeal fracture fixation," J. Biomech., 14(6), pp. 377-387 (1981) - poly(levo lactic acid) "PLLA" rods;
P. Christel et al. "Biodegradable composites for internal fixation," in Advances in Biomaterials 3, Biomaterials 1980, ed. G. D. Winter et al. 3, 1982, pp. 271-280 - combinations of poly(d/l lactic acid) "PDLLA" and PLLA, as well as polyglycolic acid "PGA";
M. Vert et al. "Bioresorbable plastic materials for bone surgery," Macromolecular Biomaterials ed. Hastings et al. 1984, pp. 120-142 - combinations of "PDLLA" and PLLA;
D. Lewis et al. "Absorbable fixation plates with fiber reinforcement", Trans. Soc. Biomater., 4, p. 61 (1981) - PDLLA reinforced with alumina, alumina-boriasilica and carbon;
J. Kilpikari et al "Carbon fibre reinforced biodegradable and non-biodegradable polymers as bone plate materials," Trans. Soc. Biomater., 7, p. 242 (1984) - PGA/PLA copolymers with and without carbon reinforcement;
L. Claes et al. "Refixation of osteochondral fragments with resorbable polydioxanone pins in animal experiments", Trans. Soc. Biomater., 8, p. 163 (1985) - the poly(ethyl ether) polydioxanone;
R. H. Wehrenberg, "Lactic acid polymers: strong, degradable thermoplastics," Mater. Eng., 94 (3), pp. 63-66 (1981) - copolymers of L-lactide and epsilon-caprolactone, as well as polycaprolactone "PCL";
X. D. Feng et al. "Synthesis and evaluation of biodegradable block copolymers of epsilon-caprolactone and d,l-lactide," J. Polym. Sci.: Polym. Letters Ed., 21, pp. 593-600 (1983) - PCL and various PCL/PDLLA copolymers;
V. Sknondia et al. "Chemical and physicomechanical aspects of biocompatible orthopedic polymer (BOP) in bone surgery," J. Int. Med. Res., 15 (5), pp. 293-302 (1987) - N-vinylpyrollidone/methylmethacrylate copolymers;
A. C. Ibay et al. "Synthesis and properties of polymers for biodegradable implants," Polym. Mater. Sci. Eng., 53, pp. 505-507 (1985)- polypropylene fumarate;
J. Kohn et al. "Poly(iminocarbonates) as potential biomaterials." Biomaterials, 7(3), pp. 176-182 (1986) - polyiminocarbonate;
A. J. Owen, "Some dynamic mechanical properties of microbially produced poly-beta-hydroxybutyrate/betahydroxyvalerate copolymers," Colloid & Polymer Science, 263, pp. 799-803 (1985), among several - copolymers of polyhydroxybutrate/polyhydroxyvalerate;
S. W. Shalaby et al. "Absorbable polyesters with structure modulated biological properties," Trans. Soc. Biomater., 8, p. 212 (1985) - polyalkylene oxalates; and
L. Claes et. al. "Resorbable implants for the treatment of bone defects," Trans. Soc. Biomater., 11, p. 499 (1988) - polyester-amide.
Typical fibers used as reinforcements in these composites are carbon fibers and other nondegradable materials, biodegradable inorganic polymers and biodegradable organic polymers. Some of the reinforcements used in these prior studies have been nonerodible--for example, carbon fibers, glass filaments and the like. While these materials can give dramatic increases in initial strength to composites over their polymer matrix alone they have the medically unacceptable problem of leaving behind finely divided nondegradable debris when the substrate disappears and also sometimes giving rise to rapid losses of strength during environmental exposure. Typical biodegradable polymers include self-reinforcement where the reinforcement is made of polymers of the same material as the polymer matrix but with the reinforcing polymer having a high degree of orientation of polymer chains for increased strength. In other cases one organic material, for example poly(glycolic acid) fibers, can be used in another organic material such as poly(lactic acid).
While the advantages of biodegradable supports are quite clear, especially their elimination of the need to perform a second surgical procedure to remove them, there are still advances to be made. A major area of interest involves identifying materials which have a proper balance of strength and bioerosion.
This balance is a fine one. For example, much of the work carried out heretofore has focused on PLLA and PDLLA. These two materials, while chemically closely related, with one a pure material and the other a mixture of two enantiomers of the same compound, illustrate the balance point. Pure PLLA is quite strong, having a tensile strength of about 60 MPa in one type of test. PDLLA has a tensile strength of about 40 MPa in the same test, with copolymers falling between these two values. Thus, one could achieve different levels of strength by varying the ratio of the comonomer units. The erosion properties of these materials also vary as a function of composition. Pure PLLA is very durable, or nondegradable, depending on the user's point of view. It retains nearly all of its physical integrity after 150 days of implantation. The same study reported that a 50--50 PLLA-PDLLA copolymer degraded to 31% of its initial strength in 30 days of implantation. Many workers in the field have looked at the physical and erosion properties of erodible or degradable polymers, each seeking a composite system which will have physical support properties which lead to optimal healing and degradation properties which lead to prompt clearance of the implant from the system without any premature degradation which would compromise the desired physical properties.